Work from this laboratory has advanced the general hypothesis that inheritance of low abundance alleles of mitochondrial (as opposed to chromosomal) genes may offer an explanation for the occurrence of disorders such as Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Alzheimer's disease (AD) which have not been analyzable in terms of conventional Mendelian genetics and which have consequently been labeled "sporadic". This project will investigate the specific hypothesis that AD is a systemic, genetically determined illness which results from a primary dysfunction of cytochrome oxidase (complex IV) and that this defect is derived via the mitochondrial genome. Cytochrome oxidase will be purified from AD brain tissue obtained at autopsy and will be studied using a variety of biochemical techniques with the goal of determining whether or not there are intrinsic abnormalities in AD cytochrome oxidase as compared to controls. Simultaneously, we will sequence the mitochondrial genes encoding cytochrome oxidase subunits with the aim of determining whether or not there are indeed consistent sequence abnormalities of mitochondrial DNA in AD patients which might account for the observed biochemical abnormalities. We will transplant mitochondria from cultured fibroblasts from AD patients into control cell lines whose mitochondria have been deleted (with ethidium bromide) and assay the resulting biochemical phenotype in order to determine whether or not the defects in cytochrome oxidase are wholly or partially determined by the mitochondrial genome. If successful, this project will provide fundamental information about the causation of AD, new insights into basic mechanisms of aging, and validate the general concept of mitochondrial inheritance as a model for numerous other "sporadic" disorders.